Infection is one of the leading causes of morbidity and mortality in the elderly. Streptococcus pneumoniae is the organism most commonly isolated from elderly patients with pneumonia. Increased susceptibility to infections that occur in the elderly has been attributed to deteriorating health, decreased pulmonary function and a functional decline of the immune system. The immune system is unique in that it may be manipulated to achieve a desirable response. Studies in aged mice demonstrate both quantitative and qualitative changes in the immune response to T-independent type 2 (TI-2) antigens. Reports indicate age related loss of affinity, fine specificity and protective immunity are associated with a molecular shift in V gene usage and changes in cytokine profile. Studies of the in vivo immune response in elderly have been limited to vaccine efficacy studies and quantitative analysis of the magnitude and duration of the post-vaccination antibody response. The results of these studies suggest that despite adequate quantitative immune response the elderly show decreased vaccine efficacy. Current knowledge concerning the aging immune response to TI-2 antigens is mostly based on animal models and may not be applicable to humans. Human studies are fragmented and address quantitative and qualitative immune response as separate issues. We propose to study and characterize the immune response to S. pneumoniae capsular polysaccharide in the elderly. We will focus on both quantitative and qualitative changes in the immune response on molecular and functional levels. The quantitative immune response, isotype and IgG subclass, will be correlated with opsonophagocytic activity. We hypothesize that the discrepancy between the quantitative and qualitative immune response in the elderly results from altered V region sequence. We will characterize the immunoglobulin gene usage pattern and V-D-J joint diversity of the antibody response to pneumococcal polysaccharides (PPS) of serotypes 4 and 14 in elderly and young adults. This will be accomplished by gene family specific ELISA and by isolating single responding cells and determining the sequence of the V chains. Second, we propose to evaluate the influence of soluble regulatory factors on the aging immune response. The reconstituted SCID mouse model will be used to study the aging human B cell response to PPS 4 and 14 in a controlled cytokine environment allowing us to differentiate altered response intrinsic to the B cells versus altered responses secondary to environmental factors such as cytokines. The results of these studies will form the essential baseline for the rational development of vaccine and adjuvant strategies for the elderly.